Total synthesis of natural products

Total Synthesis of Natural Products


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Jie Jack Li • E.J. Corey
Editors

Total Synthesis of Natural
Products
At the Frontiers of Organic Chemistry


Editors
Jie Jack Li
New Jersey
USA

E.J. Corey
Harvard University
Dept. of Chemistry and Chemical Biology
Cambridge
USA

ISBN 978-3-642-34064-2
ISBN 978-3-642-34065-9 (eBook)
DOI 10.1007/978-3-642-34065-9
Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2012955413

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Dedicated to
Professor David Y. Gin (1967–2011)


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Preface

The last few decades have witnessed some exciting developments of synthetic
methodologies in organic chemistry. Chiefly among these developments are ringclosing metathesis (RCM) and transition metal-catalyzed C–H activation, which
have emerged as novel and useful tools.
A touchstone for any synthetic methodology is how practical it is in synthesis,
especially total synthesis of natural products. Therefore, it is not surprising that
books on total synthesis occupy a place on nearly every organic chemist’s
bookshelf.
This volume is somewhat different from previous books on total synthesis. We
have been fortunate enough to enlist eleven current practitioners in the field of total
synthesis to describe one of their best total syntheses. These authors leveraged
synthetic methodologies developed in their own laboratories as key operations in
their construction of natural products. As such, this book reflects a true sense of
what is happening at the frontiers of organic chemistry.
Skillman, NJ, USA
Cambridge, MA, USA

Jie Jack Li
E.J. Corey

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Contents

1

2

3

Nominine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Kevin M. Peese and David Y. Gin
1.1 Introduction and Classification . . . . . . . . . . . . . . . . . . . . . . . . .
1.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4 Previous Synthetic Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4.1 Total Synthesis of Nominine [19a] . . . . . . . . . . . . . . . . .
1.4.2 Synthetic Studies Toward the Hetisine Alkaloids . . . . . . .
1.5 Strategy and Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.6 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.7 Complete Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nakiterpiosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Shuanhu Gao and Chuo Chen
2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Synthesis of the 6,6,5,6 Steroidal Skeleton . . . . . . . . . . . . . . . . .
2.2.1 The Biomimetic Approaches . . . . . . . . . . . . . . . . . . . . .
2.2.2 The Ring-by-Ring Approaches . . . . . . . . . . . . . . . . . . . .
2.2.3 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Synthesis of Nakiterpiosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4 Biology of Nakiterpiosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The Kinamycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Seth B. Herzon
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.2 Structure Elucidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3 Biological Activity and Mechanism of Action Studies . . . . . . .
3.4 Biosyntheses of the Kinamycins . . . . . . . . . . . . . . . . . . . . . . .

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9
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4

5

3.5

Syntheses of the Kinamycins . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.1 Synthesis of (À)-Kinamycin C [24] . . . . . . . . . . . . . . .
3.5.2 Synthesis of (Ỉ)-O-Methyl-Kinamycin C [32] . . . . . . . .
3.5.3 Syntheses of (À)-Kinamycins C, F, and J [39] . . . . . . . .
3.5.4 Synthesis of (À)-Kinamycin F [45] . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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59
64

A Short Synthesis of Strychnine from Pyridine . . . . . . . . . . . . . . .
David B. C. Martin and Christopher D. Vanderwal
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Synthesis of Strychnine: A Historical Perspective . . . . . . . . . .
4.3 Structural Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4 Background: Zincke Aldehydes . . . . . . . . . . . . . . . . . . . . . . .
4.5 Background: Intramolecular Cycloadditions of Indoles . . . . . .
4.6 Development of the Intramolecular Diels–Alder Cycloaddition
of Tryptamine-Derived Zincke Aldehydes . . . . . . . . . . . . . . .
4.7 Synthesis of Norfluorocurarine . . . . . . . . . . . . . . . . . . . . . . .
4.8 Protecting Groups Are Not Always Evil . . . . . . . . . . . . . . . . .
4.9 Strategies for D-Ring Formation for Strychnine . . . . . . . . . . .
4.10 Some Unusual Approaches to C15–C20 Bond Formation . . . .
4.11 A Successful Route to Strychnine . . . . . . . . . . . . . . . . . . . . .
4.12 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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92

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98
99

Bryostatin 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Yu Lu and Michael J. Krische
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4 Previous Synthetic Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.1 Total Synthesis of Bryostatin 7 (Masamune 1990) . . . . . .
5.4.2 Total Synthesis of Bryostatin 2 (Evans 1998) . . . . . . . . .
5.4.3 Total Synthesis of Bryostatin 3 (Nishiyama
and Yamamura 2000) . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.4 Total Synthesis of Bryostatin 16 (Trost 2008) . . . . . . . . .
5.4.5 Synthesis of Bryostatin 1 (Keck 2011) . . . . . . . . . . . . . .
5.4.6 Synthesis of Bryostatin 9 (Wender 2011) . . . . . . . . . . . .
5.5 Strategy and Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.1 Synthesis of A-Ring Fragment 68 . . . . . . . . . . . . . . . . . .
5.6.2 Synthesis of C-Ring Fragment 69 . . . . . . . . . . . . . . . . . .
5.6.3 Fragment Union and Total Synthesis of Bryostatin 7 . . . .
5.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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103
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106
108

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Contents

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7

8

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Serratezomine A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Julie A. Pigza and Jeffrey N. Johnston
6.1 Introduction and Classification . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.4 Previous Synthetic Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.1 Total Synthesis of Serratinine . . . . . . . . . . . . . . . . . . . . .
6.4.2 Synthetic Approaches Towards the Framework of
Serratinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5 Strategy and Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.6 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.7 Complete Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

131
131
132
133
136
136
138
139
141
152
152

Hypocrellin/Cercosporin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Carol A. Mulrooney, Erin M. O’Brien, and Marisa C. Kozlowski
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2 Biological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3 Previous Synthetic Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.1 Synthesis of (À)-Phleichrome and (À)-Calphostin
A,D [30] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.2 Synthesis of (À)-Calphostin D [31] . . . . . . . . . . . . . . . . .
7.3.3 Synthesis of (À)-Phleichrome and (À)-Calphostin A

[32a] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.4 Synthesis of (À)-Calphostin A–D [33a] . . . . . . . . . . . . .
7.4 Conformational Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.5 Strategy and Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.1 Synthesis of (À)-Hypocrellin A . . . . . . . . . . . . . . . . . . .
7.6.2 Synthesis of (+)-Phleichrome and (+)-Calphostin D . . . . .
7.6.3 Synthesis of (+)-Cercosporin . . . . . . . . . . . . . . . . . . . . .
7.7 Synthesis of Perylenequinone Analogs . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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170
170
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174
175
179

Phomactin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Yu Tang, Kevin P. Cole, and Richard P. Hsung
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.1 Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.2 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.3 Medicinal Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . .

8.1.4 Synthetic Challenges . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2 The Architecturally Distinctive ABD-Tricycle . . . . . . . . . . . . .
8.2.1 Retrosynthetic Analysis . . . . . . . . . . . . . . . . . . . . . . . .
8.2.2 Approaches to the Oxa-Annulation Precursor . . . . . . . .
8.2.3 An Improved Synthesis of Oxa-Annulation Precursor . .

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Contents

8.2.4 Key Oxa-Annulation and the D-Ring Atropisomerism . . .
8.2.5 A Formal Synthesis of (À)-Phomactin A . . . . . . . . . . . . .
8.3 Lessons Learned from the Challenging Structural Topology . . . .
8.3.1 Oxidations of C3 and C3a in B-Ring . . . . . . . . . . . . . . .
8.3.2 Reduction of C8a and C8b at the AB-Ring Junction . . . .
8.3.3 Homologation at C5a in the A-Ring . . . . . . . . . . . . . . . .
8.4 Completion of the Total Synthesis . . . . . . . . . . . . . . . . . . . . . . .
8.4.1 The Diene Route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4.2 The Allyl Alcohol Route . . . . . . . . . . . . . . . . . . . . . . . .
8.4.3 The Vinyl Epoxide Route . . . . . . . . . . . . . . . . . . . . . . . .
8.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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194
195
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207

(+)-11,110 -Dideoxyverticillin A . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Justin Kim and Mohammad Movassaghi
9.1 Introduction and Classification . . . . . . . . . . . . . . . . . . . . . . . . .
9.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.3 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.4 Previous Synthetic Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.4.1 Previous Approaches to the C3–C30 Dimeric Linkages . . .
9.4.2 Previous Approaches to the Epidithiodiketopiperazine
Motif . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.4.3 Total Synthesis of Epidithiodiketopiperazine Alkaloids . .
9.5 Strategy and Retrosynthesis for (+)-11,110 -Dideoxyverticillin A .
9.5.1 Synthesis of (+)-11,110 -Dideoxyverticillin A . . . . . . . . . .
9.5.2 Generalization to the Epipolythiodiketopiperazine
Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

211

Retigeranic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
David R. Adams and Toma´sˇ Hudlicky´
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10.2 Isolation and Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.4 Approaches to Total Synthesis . . . . . . . . . . . . . . . . . . . . . . . .
10.4.1 Hudlicky . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.4.2 Fallis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.4.3 Fraser-Reid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.4.4 Trauner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.5 Total Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.5.1 Corey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.5.2 Paquette . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.5.3 Wender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.5.4 Hudlicky . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.6 Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contents

11

Total Synthesis of the Lycopodium Alkaloid Complanadine A . . .
Richmond Sarpong and Daniel F. Fischer
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.3 Biological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.4 The Siegel Synthesis of Complanadine A . . . . . . . . . . . . . . . .
11.5 Strategy and Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . .
11.6 Borylative C–H Functionalization . . . . . . . . . . . . . . . . . . . . .
11.6.1 Benzene Ring Functionalization: Hartwig Synthesis
of Taiwaniaquinol B . . . . . . . . . . . . . . . . . . . . . . . .
11.6.2 Pyrrole Ring Functionalization: Gaunt Synthesis
of Rhazinicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.6.3 Indole Ring Functionalization: Movassaghi
Synthesis of the Asperazine Core . . . . . . . . . . . . . . .
11.7 Completion of the Complanadine A Synthesis . . . . . . . . . . . .
11.8 Application of the Strategy to Lycopladines F and G . . . . . . .
11.9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273


.

List of Contributors

Chuo Chen Department of Biochemistry, Southwestern Medical Center, University of Texas, Dallas, TX, USA
Kevin P. Cole School of Pharmacy and Department of Chemistry, University of
Wisconsin, Madison, WI, USA
Daniel F. Fischer Department of Chemistry, University of California, Berkeley,
CA, USA
Shuanhu Gao Department of Biochemistry, Southwestern Medical Center, University of Texas, Dallas, TX, USA
David Y. Gin Molecular Pharmacology and Chemistry Program, Memorial SloanKettering Cancer Center, New York, NY, USA
Seth B. Herzon Yale University, New Haven, CT, USA
Richard P. Hsung School of Pharmacy and Department of Chemistry, University
of Wisconsin, Madison, WI, USA
Jeffrey N. Johnston Department of Chemistry, Institute of Chemical Biology,
Vanderbilt University, Nashville, TN, USA
Justin Kim Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, MA, USA
Marisa C. Kozlowski Department of Chemistry, University of Pennsylvania,
Philadelphia, PA, USA
Michael J. Krische Department of Chemistry and Biochemistry, University of
Texas, Austin, TX, USA
Yu Lu Department of Chemistry and Biochemistry, University of Texas, Austin,
TX, USA
David B. C. Martin Department of Chemistry, University of California, Irvine,
CA, USA
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List of Contributors

Mohammad Movassaghi Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, MA, USA
Carol A. Mulrooney Department of Chemistry, University of Pennsylvania,
Philadelphia, PA, USA
Erin M. O’Brien Department of Chemistry, University of Pennsylvania,
Philadelphia, PA, USA
Kevin M. Peese Discovery Chemistry, Bristol-Myers Squibb Company,
Wallingford, CT, USA
Julie A. Pigza Department of Chemistry, Queensborough Community College,
Bayside, NY, USA
Richmond Sarpong Department of Chemistry, University of California,
Berkeley, CA, USA
Christopher D. Vanderwal Department of Chemistry, University of California,
Irvine, CA, USA
Yu Tang School of Pharmacy and Department of Chemistry, University of
Wisconsin, Madison, WI, USA


Chapter 1

Nominine
Kevin M. Peese and David Y. Gin

H

H

Me
N

H

OH
H

CH2

H
nominine

1.1

Introduction and Classification

The genera of Aconitum (commonly known as Monkshood) and Delphinium, and to
a lesser extent Rumex, Consolida, and Spiraea, have long been recognized as a rich
source of alkaloid natural products [1]. The diterpenoid alkaloids are generally
classified into two major groups: the C19-diterpenoid alkaloids (sometimes referred
to as the C19-norditerpenoid alkaloids) and the C20-diterpenoid alkaloids. Within
the C20-diterpenoid alkaloids, at least 11 separate classes have been isolated,
including the hetisine alkaloids (Chart 1.1).
Among the first hetisine alkaloids isolated were nominine (1) [2], kobusine (2) [3],
pseudokobusine (3) [4], hetisine (4) [5], and ignavine (5) [6] in the 1940s and 1950s
(Chart 1.2). Since these early isolations, over 100 distinct hetisine alkaloids have
K.M. Peese (*)
Discovery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford,
CT 06492, USA

e-mail:
D.Y. Gin
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center,
1275 York Avenue, New York, NY 10065, USA
J.J. Li and E.J. Corey (eds.), Total Synthesis of Natural Products,
DOI 10.1007/978-3-642-34065-9_1, # Springer-Verlag Berlin Heidelberg 2012

1


2

K.M. Peese and D.Y. Gin

CH2

CH2

RN

CH2

Me

Me

RN

RN
RN

Me

Me

Me
veatchines

napellines

CH2

tricalysiamides

O

CH2

RN
OHC

Me
denutadines

racemulosines

Me

O

CH2

RN

N

RN

Me

Me

Me

vakognavines

kusnezolines

CH2

acrutines

CH2

CH2

N

RN
Me

RN

Me
atisines

Me
hetisines

hetidines

Chart 1.1 C20-diterpenoid alkaloids

CH2
HO

N

13

OH

R1

H

OH

H
Me R2

nominine (1) (R1, R2 = H)
kobusine (2) (R1= OH; R2 = H)
pseudokobusine (3) (R1, R2= OH)

1

HO

HO

N

N
BzO
H
Me H

hetisine (4)

12

CH2

CH2
OH

H
Me H

ignavine (5)

OH

2

N

3

4

19

20

11
14

9

17

CH2
16
15

10

8
7

5
6

Me

18

hetisine
skeleton (6)

Chart 1.2 Hetisine alkaloids

been isolated and characterized with new alkaloids continuing to be discovered.
Structurally, the hetisines are characterized by a highly fused heptacyclic ring system
with an embedded tertiary nitrogen core. The separate members of the hetisine
alkaloids are distinguished by the number, location, and stereochemical placement
of oxygen functionality, primarily alcohols and simple esters.

1.2

Pharmacology

The hetisine alkaloids have long been recognized to be active constituents of
traditional eastern herbal medicines [7]. Pharmacological investigations of the
hetisine alkaloids have shown a diverse range of bioactivities [1b, 7]. Significantly,
guan-fu base A (7) is reported to be under clinical development in China for
arrhythmia [1a]. In addition, kobusine (2), pseudokobusine (3), as well as multiple

1 Nominine
Chart 1.3
Pharmacologically significant
hetisine alkaloids

3
BzO

AcO
HO
AcO
N

CH2
OH
OH

H
Me H
guan-fu base A (7)

HO
AcO

HO
CH2
OH

N
H

Me H
zeravshanisine (8)

AcO

HO

CH2

AcO
N
H
Me H
tadzhaconine (9)

O-acyl derivatives thereof have shown potent vasodilatory activity [8]. A number of
other hetisine alkaloids have shown diverse biological activities. These include
nominine [9] (1) (local anesthetic, anti-inflammatory, and antiarrhythmic), hetisine
[9a] (4) (hypotensive), ignavine [10] (5) (analgesic, anti-inflammatory, antipyretic,
sedative, antidiuretic), zeravshanisine [9a] (8) (antiarrhythmic and local anesthetic), and tadzhaconine [9a, 11], (9) (antiarrhythmic) (Chart 1.3).

1.3

Biosynthesis

The biosynthesis of the atisane class of C20-diterpene alkaloids, including the
hetisine family, has been proposed to take place in two principal phases [1a]. The
first phase encompasses biogenesis of most of the diterpene framework via a
standard, diterpene biosynthesis (Scheme 1.1) [12]. Beginning with geranylgeranyl
diphosphate (10), cyclization with ent-copalyl diphosphate synthase produces

ent-copalyl diphosphate (11). The exocyclic alkene of 11 then undergoes annulation with the allylic diphosphate to afford, after a series of carbocation
rearrangements, ent-atisir-16-ene (19). Noteworthy in this cascade is the nonclassical carbocations 15 and 16. The second phase of the biosynthesis of the atisane class
has been hypothesized, but is not well understood [13]. It has been proposed that an
oxidation event occurs on ent-atisir-16-ene (19) to give a dialdehyde or its synthetic
equivalent (20). Following a condensation event with a nitrogen source and reduction, the atisine skeleton (21) of C20-diterpene alkaloids is accessed. Carbon–carbon
bond formation between C-14 and C-20, possibly through a Prins-type intermediate, produces the hetidine skeleton (22) of C20-diterpene alkaloids. Finally, bond
formation between the nitrogen and C-6 generates the hetisine-type skeleton (6).

1.4

Previous Synthetic Work

The C20-diterpene alkaloids have long served as classic targets within the field of
natural product synthesis [14]. Total syntheses of four C20-diterpene alkaloids have
thus far been reported: atisine [15], veatchine [16], garryine [17], and napelline [18].
In spite of this progress, synthetic efforts toward the hetisine alkaloids have been
relatively sparse. Prior to our work in the area, these efforts include one total synthesis
and five synthetic studies.


4

K.M. Peese and D.Y. Gin
Me
Me

OPP
Me

10

CH2

C
H

H
Me

C
H

H
Me

17

H
Me

12

H
C
H

Me

[1,2-hydride shift]
Me

Me

H
Me

13

Me
Me

CH

H
C
H

Me

H
Me

H
Me

CH2

"nitrogen"
RN

H
OHC

H
Me

CH

14

CH2
OHC

Me

H

15
non classical carbocation

[oxidation]

H
Me
19

H
Me

H

H

18

H
Me

CH2

Me

H
Me

H
Me

CH2

16
non classical carbocation
H
CH2

Me

CH2

Me

Me

CH2

H
Me

Me

H
Me

Me

Me

Me

OPP

H
ent - copalyl
diphosphate Me MeH
synthase
11

Me
Me

Me

Me

Me
Me

H
Me

20

21

[C -C formation]

CH2
N
H
Me

CH2
[C -N formation]

hetisine core (6)

RN
H
Me

22

Scheme 1.1 Postulated biosynthesis of hetisine alkaloids

1.4.1

Total Synthesis of Nominine [19a]

In 2004, Muratake and Natsume reported the landmark total synthesis of
(Ỉ)-nominine (1), the first total synthesis of a hetisine alkaloid (Scheme 1.2) [19].
Their approach was based upon two key reactions: a-arylation of an aldehyde [20] for
formation of the C-9 and C-10 carbon–carbon bond (i.e., 24!25) and Lewis acidcatalyzed acetal-ene reaction [21] for formation of the key C-14 and C-20
carbon–carbon bond (i.e., 26!27). Beginning with 3-methoxyactetic acid (23), aryl
bromide aldehyde 24 was prepared in a straightforward nine-step sequence. In the first
key reaction of the synthesis, treatment of aryl bromide 24 with PdCl2(PPh3)2 and
Cs2CO3 in refluxing THF-delivered tricyclic 25 in 65 % yield, 4.2:1 dr. Next,
elaboration through a six-step sequence produced intermediate alkene 26. Acetalene reaction of 26 using BF3·OEt2 in toluene at À18  C afforded ether 27 in 66 % after
subsequent deketalization with p-TsOH in acetone. Installation of the nitrogen atom
began six steps later with the conjugate cyanation of enone 28 with Et2AlCN (Nagata
reagent) [22] in toluene resulting in b-cyanoketone 29. Then, following protection of
the ketone as the TMS enol ether, the cyano group was reduced to the primary amine


1 Nominine

5

Muratake & Natsume (2004)

HO

MeO
OHC

OMe

OMe
OHC

PdCl2(PPh3)2,

Br

H

Cs2CO3, D

O
O

O

O

23

O

24

OMOM

25

OH
O
OPiv

O

OPiv

O

H

H

TsOH

H

acetal-ene reaction
Me

O

O

28

O

BF3•OEt2;

H

O

H
OPiv

O

27

26

Et2AlCN
OMOM

OMOM
OPiv

O

H
NC

H
Me O

1. LDA; TMSCl
2. LiAlH4

OH
OH

O
Cbz

Cbz
N

3. CbzCl, Et3N
4. NaCNBH3

N

H

H
Me

29

H

O

H

H
31
Me

30

radical
cyclization

Bu3SnH, AIBN, D;
SiO2
OH
CH2
N
H
Me

1. Et3SiH,
Pd(OAc)2

OH
2. SOCl2, py
3. K2CO3, D
nominine (1)

HO

CH2

N

OAc

Cbz

H
Me

H

N
33

CH2

O
Cbz

H
Me

H
32

Scheme 1.2 Total synthesis of nominine, first total synthesis of a hetisine alkaloid

with LiAlH4. The amine was condensed with the proximal ketone functionality to
furnish the enamine which was immediately protected with a Cbz group leading to the
protected enamine. Reduction of the enamine with NaCNBH3 produced Cbzprotected pyrrolidine 30. Following a ten-step interlude to complete construction of

the [2.2.2] bicyclo-octane system, completion of the aza-ring system was addressed.
Deprotection of the Cbz group of 33 was accomplished with Et3SiH, Pd(OAc)2, and
NEt3. The last critical C–N bond of the pyrrolidine was then formed via alkylation of
the amine with the adjacent alcohol by first activation of the alcohol with SOCl2 and
then annulation. The synthesis was then completed with the deprotection of the allylic
acetate to the allylic alcohol with K2CO3 in refluxing methanol-giving nominine.
Overall, Muratake and Natsume were able to accomplish a 40-step synthesis of
(Ỉ)-nominine in 0.15 % yield.


6

K.M. Peese and D.Y. Gin
van der Baan and Bickelhaupt (1975)

OH
EtN

CH2 1. NBS,
H2O

EtN

2. heptane,
reflux

O

OTHP

O

1. AllylBr,
NaH

CN 34
Claisen rearrangement

CN

THPO

NaH

EtN

EtN

2. DHP,
TsOH

O

O

Br

O

O

35

CN

O

CN 36

37

Shibanuma and Okamoto (1985)
H2N
Pb(OAc)4;

hn,

1. Ra-Ni
Cbz

N

ClN

Me Me
38

Me Me

Cl

Me Me

39

N

TFA

2. NCS

CbzCl

Me

40

41

Hofmann-Löffler-Freytag
reaction
Winkler and Kwak (2001)

O

NBoc
hn
O

Me

42

[2+2]
photo
cycloaddition

43

Me

EtOH,

NBoc

reflux

O

Me

O

PPTs
Boc

N

NBoc

retro-Mannich reaction

45

Mannich reaction

44

Williams and Mander (2003)
OMe

OMe

Br
CH2O,
O
CO2Et

Me

MeNH2, D
Mannich reaction

46

N

Br
O
CO2Et

Me

N

OAc

Br

Ag+

OH
OAc 48

47

Me

OAc

N
OH
OAc 49

Hutt and Mander (2005)

TBSO

O

O

TBSO

FeCl3, TMSCl

DDQ
H
N

MeO

H
Me

H
N

MeO

O

H
Me

H
Me

51

52

O
50

TBSO
MeO2C
N

O

H

Scheme 1.3 Previous synthetic studies

1.4.2

Synthetic Studies Toward the Hetisine Alkaloids

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from
pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular
alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation
with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with N-bromosuccinimide
and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP)
ether produced bromide 36, which was then cyclized in an intramolecular fashion to
give tricylic 37.


1 Nominine

7

Ten years later in 1985, Shibanuma and Okamoto reported the synthesis of
pentacyclic intermediate 41 (Scheme 1.3) [24]. This approach to the hetisine alkaloids,
a refinement of work previously reported by Okamoto [25], utilized a HofmannLoăfflerFreytag reaction to form the polycyclic substructure surrounding the tertiary
amine of the hetisine alkaloids. In the key sequence of the synthesis, styrene 38 was
subjected to lead tetraacetate [Pb(OAc)4] oxidation to give an aziridine which was
immediately fragmented by treatment with benzyl chloroformate (CbzCl) to give
benzylic chloride 39. Reductive cleavage of the benzylic chloride and concomitant
cleavage of the carbamate with Raney nickel followed by N-chlorination of the amine
provided the key HofmannLoăfflerFreytag precursor N-chloramine 40. Photolysis in
acidic media provided the HofmannLoăfflerFreytag reaction product 41.
More recently in 2001, Winkler and Kwak reported methodology designed to
access the pyrrolidine core of the hetisine alkaloids via a photochemical [2+2],
retro-Mannich, Mannich sequence (Scheme 1.3) [26]. In a representative example
of the methodology, vinylogous amide 42 was photo-irradiated to give the [2+2]
cycloaddition product 43. Heating cyclobutane 43 in ethanol provided enamine 44
via a retro-Mannich reaction. Exposure of enamine 44 to acidic conditions then
effected a Mannich reaction, resulting in pyrrolidine 45.
In 2003, Williams and Mander reported a method designed to access the hetisine
alkaloids (Scheme 1.3) [27]. This approach, based upon a previously disclosed
strategy by Shimizu et al. [28], relied on arylation of a bridgehead carbon via a
carbocation intermediate in the key step. Beginning with b-keto ester 46, double
Mannich reaction provided piperidine 47. Following a straightforward sequence,
piperidine 47 was transformed to the pivotal bromide intermediate 48. In the key
step, bromide 48 was treated with silver (I) 2,4,6-trinitrobenzenesulfonate in nitromethane (optimized conditions) to provide 49 as the most advanced intermediate of
the study, in 54 % yield.
Finally in 2005, Hutt and Mander reported their strategy for the synthesis of
nominine (Scheme 1.3) [29]. The approach relies upon construction of the steroidal
ABC carbocyclic ring structure followed by stepwise preparation of the fused azaring system. In the key sequence of the synthetic study, enone 50 was oxidized
to dienone 51 with DDQ followed by Lewis acid-catalyzed intramolecular conjugate addition of the methylcarbamate to the newly formed dienone to deliver

pyrrolidine 52.

1.5

Strategy and Retrosynthesis

The highly fused and bridged architecture of the carbon–nitrogen skeleton within
the hetisine alkaloids presents a formidable challenge for the synthetic chemist.
While the placement and orientation of the oxygen functionalities of the various
hetisine alkaloids presents its own hurdles, the key synthetic challenge of the
hetisine family, exemplified by nominine as the simplest member, is construction
of the polycyclic ring system, especially the scaffold surrounding the nitrogen.


8

K.M. Peese and D.Y. Gin
13
12
20 11
1
9
2

4

3
19

14

16

18

3

Me

15

10

N

Key Elements for Retro-Cycloaddition

17

CH2

4

8
7

5

19

6

Me

1

2

10 9

5

6

N

7

11
8

20
14

Me

CH2

15 16 17
12

N

CH2
pyrrolidine
dipolar
cycloaddition

13

18

[2.2.2] bicyclo-octane
intramolecular
Diels-Alder

Chart 1.4 Key strategic retrosynthetic elements

(A)

Me
N
54

(B)

Me

intramolecular
Diels -Alder

N
53

N
57

dipolar
cycloaddition

dipolar
cycloaddition
56

Me
N

59

Me

Me
N

N
55

Me

CH2

intramolecular
Diels -Alder

N
Me

58

Scheme 1.4 Retrosynthetic analysis

Intramolecular cycloadditions are among the most efficient methods for the
synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine
skeleton encompasses two key retro-cycloaddition key elements: (1) a bridging
pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a
[2.2.2] bicyclo-octane accessible via a [4+2] Diels–Alder carbocyclic cycloaddition
(Chart 1.4). While intramolecular [4+2] Diels–Alder cycloadditions to form [2.2.2]
bicycle-octane systems have extensive precedence [3+2], azomethine dipolar
cycloadditions to form highly fused aza systems are rare [31–33]. The staging of
these two operations in sequence is critical to a unified synthetic plan. As the
proposed [3+2] dipolar cycloaddition is expected to be the more challenging of
the two transformations, it should be conducted in an early phase in the forward
synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C–C bond
disconnections for this transformation.
Two possible intramolecular disconnections are available for the [2.2.2] bicyclooctane ring system (path A and path B, Scheme 1.4). The choice between the initial
[4+2] disconnections A and B at first appears inconsequential leading to idealized
intermediates of comparable complexity (54 and 57). However, when the [4+2] and
[3+2] disconnections are considered in sequence, the difference becomes clear. For
path A, retrosynthetic [3+2] disconnection of intermediate 54 leads to the conceptual precursor 56, which embodies a considerable simplification. In contrast, path B
reveals a retrosynthetic [3+2] disconnection of intermediate 57 to provide the

precursor 59, a considerably less simplified medium-ring bridged macrocycle.
Thus, unification of the [3+2]/[4+2] dual cycloaddition strategy, using the staging